Background The three-dimensional genome organization is critical for gene regulation and can malfunction in diseases like cancer. As a key regulator of genome organization, CCCTC-binding factor (CTCF) has been characterized as a DNA-binding protein with important functions in maintaining the topological structure of chromatin and inducing DNA looping. Among the prolific binding sites in the genome, several events with altered CTCF occupancy have been reported as associated with effects in physiology or disease. However, hitherto there is no comprehensive survey of genome-wide CTCF binding patterns across different human cancers. Results To dissect functions of CTCF binding, we systematically analyze over 700 CTCF ChIP-seq profiles across human tissues and cancers and identify cancer-specific CTCF binding patterns in six cancer types. We show that cancer-specific lost and gained CTCF binding events are associated with altered chromatin interactions, partially with DNA methylation changes, and rarely with sequence mutations. While lost bindings primarily occur near gene promoters, most gained CTCF binding events exhibit enhancer activities and are induced by oncogenic transcription factors. We validate these findings in T cell acute lymphoblastic leukemia cell lines and patient samples and show that oncogenic NOTCH1 induces specific CTCF binding and they cooperatively activate expression of target genes, indicating transcriptional condensation phenomena. Conclusions Specific CTCF binding events occur in human cancers. Cancer-specific CTCF binding can be induced by other transcription factors to regulate oncogenic gene expression. Our results substantiate CTCF binding alteration as a functional epigenomic signature of cancer.

中文翻译：

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癌症特异性 CTCF 结合促进致癌转录失调

背景 三维基因组组织对基因调控至关重要，并且可能在癌症等疾病中出现故障。作为基因组组织的关键调节因子，CCCTC结合因子（CTCF）被认为是一种DNA结合蛋白，在维持染色质拓扑结构和诱导DNA环化方面具有重要作用。在基因组中的多产结合位点中，据报道，CTCF 占用率改变的几个事件与生理学或疾病的影响有关。然而，迄今为止，还没有对不同人类癌症的全基因组 CTCF 结合模式进行全面调查。结果 为了剖析 CTCF 结合的功能，我们系统地分析了 700 多个人类组织和癌症的 CTCF ChIP-seq 谱，并确定了六种癌症类型中的癌症特异性 CTCF 结合模式。我们表明，癌症特异性丢失和获得的 CTCF 结合事件与染色质相互作用的改变有关，部分与 DNA 甲基化变化有关，很少与序列突变有关。虽然丢失的结合主要发生在基因启动子附近，但大多数获得的 CTCF 结合事件表现出增强子活性并由致癌转录因子诱导。我们在 T 细胞急性淋巴细胞白血病细胞系和患者样本中验证了这些发现，并表明致癌 NOTCH1 诱导特异性 CTCF 结合，并且它们协同激活靶基因的表达，表明转录浓缩现象。结论 特定的 CTCF 结合事件发生在人类癌症中。其他转录因子可以诱导癌症特异性 CTCF 结合以调节致癌基因的表达。